Nociceptin receptor

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The nociceptin opioid peptide receptor (NOP), also known as the nociceptin/orphanin FQ (N/OFQ) receptor or kappa-type 3 opioid receptor, is a protein that in humans is encoded by the OPRL1 (opioid receptor-like 1) gene.[1] The nociceptin receptor is a member of the opioid subfamily of G protein-coupled receptors whose natural ligand is the 17 amino acid neuropeptide known as nociceptin (N/OFQ).[2] This receptor is involved in the regulation of numerous brain activities, particularly instinctive and emotional behaviors.[3] Antagonists targeting NOP are under investigation for their role as treatments for depression and Parkinson's disease, whereas NOP agonists have been shown to act as powerful, non-addictive painkillers in non-human primates.

Although NOP shares high sequence identity (~60%) with the ‘classical’ opioid receptors μ-OP (MOP), κ-OP (KOP), and δ-OP (DOP), it possesses little or no affinity for opioid peptides or morphine-like compounds.[4] Likewise, classical opioid receptors possess little affinity towards NOP's endogenous ligand nociceptin, which is structurally related to dynorphin A.[4]


In 1994, Mollereau et al. cloned a receptor that was highly homologous to the classical opioid receptors (OPs) μ-OR (MOP), κ-OR (KOP), and δ-OR (DOP) that came to be known as the Nociceptin Opioid Peptide receptor (NOP).[5] As these “classical” opioid receptors were identified 30 years earlier in the mid-1960s, the physiological and pharmacological characterization of NOP as well as therapeutic development targeting this receptor remain decades behind.[6][7] Although research on NOP has blossomed into its own sub-field, the lack of widespread knowledge of NOP's existence means that it is commonly omitted from studies that investigate the OP family, despite its promising role as a therapeutic target.

Mechanism and pharmacology

NOP cellular signalling partners

Like most GPCRs, NOP signals through canonical G proteins upon activation. G proteins are heterotrimeric complexes consisting of α, β, and γ subunits. NOP signals through a variety of Gα subtypes that trigger diverse downstream signaling cascades. NOP coupling to i or Gαo subunits leads to an inhibition of adenylyl cyclase (AC) causing an intracellular decrease in cyclic adenosine monophosphate(cAMP) levels, an important second messenger for many signal transduction pathways.[8][9] NOP acting through Gαi/o pathways has also been shown to activate Phospholipase A2 (PLA2), thereby initiating Mitogen-activated protein kinase (MAPK) signaling cascades.[10] In contrast to classical OPs, NOP also couples to Pertussis toxin (PTX)-insensitive subtypes Gαz, Gα14, and Gα16, as well as potentially to Gα12 and Gαs.[11][12][13] Activation of NOP's canonical β-arrestin pathway causes receptor phosphorylation, internalization, and eventual downregulation and recycling.[14][15] NOP activation also causes indirect inhibition of opioid receptors MOP and KOP, resulting in anti-opioid activity in certain tissues. Additionally, NOP activation leads to the activation of potassium channels and inhibition of calcium channels which collectively inhibit neuronal firing.[16][17][18]


Nociceptin controls a wide range of biological functions ranging from nociception to food intake, from memory processes to cardiovascular and renal functions, from spontaneous locomotor activity to gastrointestinal motility, from anxiety to the control of neurotransmitter release at peripheral and central sites.[19]

Pain circuitry

The outcome of NOP activation on the brain's pain circuitry is site-specific. Within the central nervous system its action can be either similar or opposite to those of opioids depending on their location.[19] In animal models, activation of NOP in the brain stem and higher brain regions has mixed action, resulting in overall anti-opioid activity. NOP activation at the spinal cord and peripheral nervous system results in morphine-comparable analgesia in non-human primates.

Reward circuitry

NOP is highly expressed in every node of the mesocorticolimbic reward circuitry. Unlike MOP agonists such as codeine and morphine, NOP agonists do not have reinforcing effects. Nociceptin is thought to be an endogenous antagonist of dopamine transport that may act either directly on dopamine or by inhibiting GABA to affect dopamine levels.[20] In animal models, the result of NOP activation in the central nervous system has been shown to eliminate conditioned place preference induced by morphine, cocaine, alcohol, and methamphetamine.[21]

Therapeutic potential

Analgesia and abuse liability

Recent studies indicate that targeting NOP is a promising alternative route to relieving pain without the deleterious side effects of traditional MOP-activating opioid therapies.[22][23][24][25][26][27] In primates, specifically activating NOP through systemic or intrathecal administration induces long-lasting, morphine-comparable analgesia without causing itch, respiratory depression, or the reinforcing effects that lead to addiction in an intravenous self-administration paradigm; thus eliminating all of the serious side-effects of current opioid therapies.[27]

Several commonly used opioid drugs including etorphine and buprenorphine have been demonstrated to bind to nociceptin receptors, but this binding is relatively insignificant compared to their activity at other opioid receptors in the acute setting (however the non-analgesic NOPr antagonist SB-612,111 was demonstrated to potentiate the therapeutic benefits of morphine). Chronic administration of nociceptin receptor agonists results in an attentuation of the analgesic and anti-allodynic effects of opiates; this mechanism inhibits the action of endogenous opioids as well, resulting in an increase in pain severity, depression, and both physical and psychological opiate dependence following chronic NOPr agonist administration.[28] Administration of the NOPr antagonist SB-612,111 has been shown to inhibit this process.[29] More recently a range of selective ligands for NOP have been developed, which show little or no affinity to other opioid receptors and so allow NOP-mediated responses to be studied in isolation.


  • AT-121 (Experimental agonist of both the µ-opioid and nociceptin receptors, showing promising results in non-human primates.)
  • Buprenorphine (partial agonist, not selective for NOP, also partial agonist of µ-opioid and δ-opioid receptors, and competitive antagonist of κ-opioid receptors)
  • BU08028 (Analogue of buprenorphine, partial agonist, agonist of µ-opioid receptor, has analgesic properties without physical dependence.) [30]
  • Cebranopadol (full agonist at NOP, μ-opioid and δ-opioid receptors, partial agonist at κ-opioid receptor)
  • Etorphine
  • MCOPPB[31] (full agonist)
  • MT-7716
  • Nociceptin
  • Norbuprenorphine (full agonist; non-selective (also full agonist at the MOR and DOR and partial agonist at the KOR); peripherally-selective)
  • NNC 63-0532
  • Ro64-6198
  • Ro65-6570
  • SCH-221,510
  • SR-8993
  • SR-16435 (mixed MOR / NOP partial agonist)
  • TH-030418



NOP agonists are being studied as treatments for heart failure and migraine[32] while nociceptin antagonists such as JTC-801 may have analgesic[33] and antidepressant qualities.[34]


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  20. Liu Z, Wang Y, Zhang J, Ding J, Guo L, Cui D, Fei J (March 2001). "Orphanin FQ: an endogenous antagonist of rat brain dopamine transporter". NeuroReport. 12 (4): 699–702. doi:10.1097/00001756-200103260-00017. PMID 11277567.
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Further reading

  • Mollereau C, Mouledous L (July 2000). "Tissue distribution of the opioid receptor-like (ORL1) receptor". Peptides. 21 (7): 907–17. doi:10.1016/S0196-9781(00)00227-8. PMID 10998524.
  • New DC, Wong YH (2003). "The ORL1 receptor: molecular pharmacology and signalling mechanisms". Neuro-Signals. 11 (4): 197–212. doi:10.1159/000065432. PMID 12393946.
  • Zaveri N (June 2003). "Peptide and nonpeptide ligands for the nociceptin/orphanin FQ receptor ORL1: research tools and potential therapeutic agents". Life Sciences. 73 (6): 663–78. doi:10.1016/S0024-3205(03)00387-4. PMC 3848886. PMID 12801588.
  • Wick MJ, Minnerath SR, Roy S, Ramakrishnan S, Loh HH (September 1995). "Expression of alternate forms of brain opioid 'orphan' receptor mRNA in activated human peripheral blood lymphocytes and lymphocytic cell lines". Brain Research. Molecular Brain Research. 32 (2): 342–7. doi:10.1016/0169-328X(95)00096-B. PMID 7500847.
  • Meunier JC, Mollereau C, Toll L, Suaudeau C, Moisand C, Alvinerie P, Butour JL, Guillemot JC, Ferrara P, Monsarrat B (October 1995). "Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor". Nature. 377 (6549): 532–5. doi:10.1038/377532a0. PMID 7566152.
  • Yung LY, Joshi SA, Chan RY, Chan JS, Pei G, Wong YH (January 1999). "GalphaL1 (Galpha14) couples the opioid receptor-like1 receptor to stimulation of phospholipase C". The Journal of Pharmacology and Experimental Therapeutics. 288 (1): 232–8. PMID 9862775.
  • Feild JA, Foley JJ, Testa TT, Nuthulaganti P, Ellis C, Sarau HM, Ames RS (October 1999). "Cloning and characterization of a rabbit ortholog of human Galpha16 and mouse G(alpha)15". FEBS Letters. 460 (1): 53–6. doi:10.1016/S0014-5793(99)01317-4. PMID 10571060.
  • Mouledous L, Topham CM, Moisand C, Mollereau C, Meunier JC (March 2000). "Functional inactivation of the nociceptin receptor by alanine substitution of glutamine 286 at the C terminus of transmembrane segment VI: evidence from a site-directed mutagenesis study of the ORL1 receptor transmembrane-binding domain". Molecular Pharmacology. 57 (3): 495–502. PMID 10692489.
  • Yung LY, Tsim KW, Pei G, Wong YH (2000). "Immunoglobulin G1 Fc fragment-tagged human opioid receptor-like receptor retains the ability to inhibit cAMP accumulation". Biological Signals and Receptors. 9 (5): 240–7. doi:10.1159/000014645. PMID 10965058.
  • Ito E, Xie G, Maruyama K, Palmer PP (December 2000). "A core-promoter region functions bi-directionally for human opioid-receptor-like gene ORL1 and its 5'-adjacent gene GAIP". Journal of Molecular Biology. 304 (3): 259–70. doi:10.1006/jmbi.2000.4212. PMID 11090272.
  • Okada K, Sujaku T, Chuman Y, Nakashima R, Nose T, Costa T, Yamada Y, Yokoyama M, Nagahisa A, Shimohigashi Y (November 2000). "Highly potent nociceptin analog containing the Arg-Lys triple repeat". Biochemical and Biophysical Research Communications. 278 (2): 493–8. doi:10.1006/bbrc.2000.3822. PMID 11097863.
  • Serhan CN, Fierro IM, Chiang N, Pouliot M (March 2001). "Cutting edge: nociceptin stimulates neutrophil chemotaxis and recruitment: inhibition by aspirin-triggered-15-epi-lipoxin A4". Journal of Immunology. 166 (6): 3650–4. doi:10.4049/jimmunol.166.6.3650. PMID 11238602.
  • Mandyam CD, Thakker DR, Christensen JL, Standifer KM (August 2002). "Orphanin FQ/nociceptin-mediated desensitization of opioid receptor-like 1 receptor and mu opioid receptors involves protein kinase C: a molecular mechanism for heterologous cross-talk". The Journal of Pharmacology and Experimental Therapeutics. 302 (2): 502–9. doi:10.1124/jpet.102.033159. PMID 12130708.
  • Thakker DR, Standifer KM (September 2002). "Orphanin FQ/nociceptin blocks chronic morphine-induced tyrosine hydroxylase upregulation". Brain Research. Molecular Brain Research. 105 (1–2): 38–46. doi:10.1016/S0169-328X(02)00390-X. PMID 12399106.
  • Spampinato S, Di Toro R, Alessandri M, Murari G (December 2002). "Agonist-induced internalization and desensitization of the human nociceptin receptor expressed in CHO cells". Cellular and Molecular Life Sciences. 59 (12): 2172–83. doi:10.1007/s000180200016. PMID 12568343.

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.